This invention relates to methods for the synthesis of high molecular weight forms of poly(propylene fumarate) having a relatively low polydispersity index. More particularly, the present invention provides methods for synthesizing poly(propylene fumarate) having molecular weights above 4,000 and polydispersity indices below 2, and more particularly below 1.8, wherein the high molecular weight poly(propylene fumarate) is synthesized in the presence of a proton scavenger.
It is often desired to replace or reconstruct all or a portion of a living bone, such as when a bone has been broken or has been resected as a result of a bone tumor. In these instances, the missing bone can be replaced with a mechanical device, such as a pin, plate or the like, or it can be replaced with an implant that is designed to more closely resemble the original bone itself. Often these implants comprise biodegradable compounds or parts made from such compounds. For example, it is known to provide porous, biodegradable compounds that contain or are coated with an osteogenic substance. It is contemplated that bone tissue will grow back into the pores of the implant and will gradually replace the entire implant as the implant itself is gradually degraded in the in vivo environment.
For obvious reasons, implants, regardless of whether they are biodegradable, should be biocompatible and non-toxic. Furthermore, the steps required for implantation of the implant (eg. the application or generation of heat and the generation of chemical by-products) should also be biocompatible and non-toxic. Also, the techniques and time periods required for implantation should be suited to the surgical environment.
Under current practices, bone implants are typically formed from a substance that is initially malleable and then becomes hard after a reasonably short period of time. Because living bone tends to atrophy and degrade in the absence of compressive stress, however, it is important that the implant not become too hard. An implant whose compressive strength is too great (i.e. an implant that is too hard) will cause stress shielding of the surrounding bone. Stress shielding in turn causes the surrounding bone to weaken and may ultimately result in catastrophic failure. Hence, the suitability of a given substance for implantation as a bone replacement depends on its biocompatibility, set time, biodegradability and ultimate compressive strength. Certain polymers have been found to be suitable in this regard.
Poly(propylene fumarate) (hereinafter xe2x80x9cP(PF)xe2x80x9d) is one such substance. P(PF) is an unsaturated linear polyester that degrades in the presence of water into propylene glycol and fumaric acid, degradation products that are cleared from the human body by normal metabolic processes. Although P(PF) is a known polymer, its routine, reproducible synthesis and the synthesis of high molecular weight forms and forms with low polydispersity indices have not previously been successfully accomplished. Known methods for the synthesis of P(PF), for example by equilibrium polycondensation, utilize reactions that are difficult to control. These synthetic methods typically require extremely high heat, the presence of a catalyst, and/or long reaction times.
Nevertheless, the fumarate double bonds in P(PF) are reactive and crosslink at low temperatures, making it valuable as an in situ polymerizable biomaterial. An effective composite mixture incorporating P(PF), a crosslinking monomer (N-vinyl pyrrolidinone), a porogen (sodium chloride), and a particulate phase (xcex2-tricalcium phosphate) can be injected into skeletal defects of irregular shape or size. As is known in the art, the mechanical properties of the cured material can be tailored by altering the ratios of the porogen and particulate phase, as well as the monomer to polymer ratio.
The maximum molecular weight Mw of the P(PF) polymer that has heretofore been reasonably achievable without encountering an unacceptably high polydispersity index is limited to less than 3,000. P(PF) polymers have been produced having Mw above 3,000, but because the degree of cross-linking varies greatly within the specimen, the polydispersity indices, (the ratio of weight average molecular weight to number average molecular weight), for these polymers are well above 2.0. Premature crosslinking of the polymer often limits the linear size or molecular weight of the linear polymer that can be achieved. It is believed that this is in part due to the fact that some of the fumarate double bonds are reaction sites for the acid-catalyzed addition of various other groups. The presence of these groups and the corresponding elimination of the double bond reduces the degree of unsaturation and thus limits molecular weight. Early attempts to mitigate this effect and increase the weight average molecular weight entailed the use of an amine to neutralize the acid, but results of this reaction were undesirable. Other early attempts included the use of buffers, and several other materials also proved ineffective.
Hence, it is highly desirable to provide an efficient, controlled synthetic reaction whereby high molecular weight linear poly(propylene fumarate) having a relatively low polydispersity index can reproducibly synthesized without regardless of whether an acid catalyst is used.
The present invention provides a method for making high molecular weight linear poly(propylene fumarate) having a relatively low polydispersity index by utilizing a relatively pure intermediate. According to the present invention, fumaryl chloride and propylene glycol are reacted in the presence of potassium carbonate, which serves as a proton scavenger, to produce bis(propyl fumarate). The reaction of fumaryl chloride and propylene glycol also produces HCl. The potassium carbonate present in the reaction solution reacts with the HCl to give water and CO2 and prevents the acid from catalyzing reactions at the fumarate double bond. According to a preferred embodiment, a mole ratio of K2CO3 to fumaryl chloride of between approximately 1.2:1 and 3:1 is used. The bis(propyl fumarate) produced according to this technique can be transesterified using conventional processing steps to yield P(PF). The P(PF) produced from bis(propyl fumarate) produced according to the present method has a higher molecular weight and is purer than P(PF) produced using previously known techniques.